WO2003097590A1

WO2003097590A1 - Method for producing bicalutamide

Info

Publication number: WO2003097590A1
Application number: PCT/EP2003/004999
Authority: WO
Inventors: Ádám Bor; György OROSZ; Ferenc Lukács; Géza Schneider
Original assignee: Helm Ag; CF Pharma Gyógyszergyártó Kft.
Priority date: 2002-05-17
Filing date: 2003-05-13
Publication date: 2003-11-27
Also published as: JP2005530795A; US7323584B2; ES2299700T3; DE50309260D1; AU2003240634A8; AU2003240634A1; EP1506170B1; PT1506170E; EP1506170A1; DE10222104A1; US20050033082A1; CA2468426A1; ATE387425T1

Abstract

The invention relates to a method for producing N-(4'-cyano-3'-trifluormethylphenyl)-3-(4''-fluorphenylsulfonyl)-2-hydroxy-2-methyl-propionamide (bicalutamide).

Description

METHOD FOR PRODUCING BICALUTAMIDE

The present invention relates to a process for the preparation of (±) -N- (4'-cyano-3'-trifluoromethyl) -3- (4 "-fluorophenylsulfonyl) -2-hydroxy-2-methyl-propionamide and its R- ( -) - and S - (+) - enantiomers.

N- (4'-Cyano-3'-trifluoromethyl) -3- (4 "-fluorophenylsulfonyl) -2-hydroxy-2-methyl-propionamide is also known under the INN name bicalutamide and belongs to the class of acylanilides. Bicalutamide has the following chemical structural formula:

The compound has an asymmetric carbon atom (*) and can therefore occur both in its racemic form as (±) bicalutamide and as an R - (-) - or S - (+) - enantiomer.

Numerous acylanilides have antiandrogenic properties and are now called nonsteroidal, peripheral antiandrogens. These compounds are for the therapy of androgen-related diseases, such as e.g. benign or malignant diseases of the prostate, hirsutism, acne etc. are suitable.

Bicalutamide has been marketed in the form of its racemate under the trade name Casodex ^® since 1995 as an agent for prostate cancer.

Acylanilides with antiandrogenic properties, which also include bicalutamide, are disclosed, for example, in EP 0 100 172. This document also describes various synthetic routes that can be summarized as read on bicalutamide as follows:

In a first synthetic route, starting from methyl methacrylate, an epoxide is first prepared that is opened with p-FIuorthiophenol with addition. After an ester cleavage, the corresponding amide is formed and in the last step the sulfide is oxidized to the sulfone using a peracid such as m-chloroperbenzoic acid (m-CPBA). This synthetic route is illustrated by the following reaction scheme:

In a second reaction path, starting from bromoacetone, the corresponding sulfide is first formed with p-fluorothiophenol, into which the acid is then introduced via a cyanohydrin reaction. After the amide formation with 3-trifluoromethyl-4-cyanoaniline, the sulfide is then oxidized again to the sulfone in the last step. This synthetic route is illustrated by the following reaction scheme:

In a further synthetic route disclosed in EP 0 100 172, the corresponding acid amide is first formed from methacryloyl chloride with 3-trifluoromethyl-4-cyanoaniline, which is then converted to an oxirane. This is opened with p-FIuorthiophenol with addition and finally the sulfide is oxidized again to the sulfone. This reaction path is illustrated by the reaction scheme below:

A synthetic route for the preparation of the two possible enantiomers of bicalutamide is disclosed in WO 98/55153. This synthesis starts from R-proline or S-proline. The correspondingly substituted propionic acid enantiomer is first obtained from this by optically induced bromolactonization. In the further course, the corresponding amide is first formed with 3-tri.luormethyl-4-cyanoaniline, before again p-fluorothiophenol under strongly basic conditions to build up the complete Molecular framework is used. Finally, the sulfide is oxidized again to the corresponding sulfone. This reaction pathway is read on R - (-) - bicalutamide and is illustrated by the following reaction scheme:

Another alternative process for the production of bicalutamide is described in WO 01/00608. This process starts from 2,3-dihydroxy-2-methyl-propionic acid and, in the course of the process, likewise reacts with 3-trifluoromethyl-4-cyanoaniline to the corresponding amide and finally with p-FIuorthiophenol to the corresponding sulfide. This is then oxidized to the desired sulfone. This synthesis is illustrated by the following reaction scheme:

Finally, WO 01/28990 discloses a process for the asymmetric synthesis of an enantiomer of an acylanilide by opening a ring structure. In the examples, bicalutamide is described by reaction with p-fluorothiophenol and subsequent oxidation of the sulfide obtained to the corresponding sulfone using m-chloroperbenzoic acid.

In principle, all of the prior art processes described above use the following reaction steps to prepare bicalutamide:

where R is the respective remaining part of the bicalutamide framework or a corresponding precursor and X is either a common leaving group, such as e.g. Cl, Br, I, MesO, TosO, etc. or together with the α-carbon atom forms a corresponding epoxide, which then adds p-FIuorthiophenol to a sulfide under basic conditions, which is then oxidized to the corresponding sulfone in the next step. As can be seen from the examples shown, this reaction sequence does not have to occur at the end of a bicalutamide synthesis, but can also be used in the middle of the reaction sequence. Likewise, the oxidation does not necessarily have to follow the formation of the sulfide immediately, but can also be carried out later. However, both individual steps are used in all bicalutamide syntheses.

However, the use of p-fluorothiophenol and the consequent necessary oxidation of the sulfide formed to the desired sulfone has numerous disadvantages. First, p-FIuorthiophenol is a toxic and highly irritating material that requires appropriate precautions to be able to use this compound on an industrial scale. Second, p-fluorothiophenol is difficult to obtain in isomerically pure form. Appropriate purification is complex. Third, a strong base is required for the addition of p-fluorothiophenol. Most synthesis processes use sodium hydride, which, however, makes the use of absolute solvents necessary and which complicates the reaction on an industrial scale due to the very high sensitivity to hydrolysis. The use of weaker bases requires the additional step of introducing a reactive leaving group. Fourthly, a strong oxidizing agent must be used to oxidize the sulfide to the sulfone. Of the abovementioned prior art mixtures of H ₂ 0 ₂ were ₍₂ S0 salt 2 KHS0 ₅ KHS0 K) described with organic acids and Oxone ^® as the oxidizing agent m-chloroperbenzoic acid. However, m-chloroperbenzoic acid is relatively expensive. Mixtures of H ₂ 0 ₂ with organic acids lead to peracids, which are used in industry Scale are dangerous to handle, and the use of Oxone ^® requires the use of phase transfer conditions that are technically complex to achieve acceptable yields.

There is therefore still a need for an economical and simple to carry out process for the preparation of bicalutamide, which preferably provides the bicalutamide either in racemic or in enantiomerically pure form. In addition, the bicalutamide should, if possible, be obtained in the purity necessary for use in medicinal products.

It is therefore an object of the present invention to provide a process for the preparation of bicalutamide which overcomes the disadvantages mentioned above.

It has now surprisingly been found that bicalutamide can be obtained in a simple manner even without the use of p-fluorothiophenol and the correspondingly necessary oxidation of the sulfide formed to the sulfone by reacting an epoxide or an epoxide precursor with a p-fluorophenyl sulfinate salt.

The present invention thus relates to a process for the preparation of bicalutamide, in which an epoxide of the general formula (I)

wherein R is a radical of the formula (II)

or is a precursor thereof, is reacted with a p-fluorophenyl sulfinate salt and, if R is a precursor of the radical of the formula (II), this is converted into a radical of the formula (II).

This reaction is illustrated by the following reaction scheme based on a reaction with the preferred sodium p-fluorophenyl sulfinate:

Alternatively, an epoxy precursor, namely a compound of the general formula (III), can be used in the process according to the invention instead of the epoxy

where R is as defined above and X is a leaving group.

The method according to the invention thus avoids the use of the toxic p-fluorothiophenol and the need for an oxidation step through the use a p-fluorophenyl sulfinate as an epoxy-opening reagent. As a result, the desired product bicalutamide or a precursor thereof which already contains the desired sulfone group is obtained directly.

The epoxide of the general formula (I) can either be used as a starting material in the process according to the invention or by a ring closure reaction from a compound of the general formula (III)

wherein R is as defined above and X is a leaving group. If desired, the epoxy obtained as an intermediate can be isolated and purified, but the reaction is preferably continued as a one-pot reaction without isolation of the epoxide. This reduces the time and effort and thus the synthesis costs and still enables the desired bicalutamide to be obtained in sufficient purity. Alternatively, as already stated above, the compound of the general formula (III) can be reacted directly with the p-fluorophenyl sulfinate salt without intermediate oxirane formation.

In the process according to the invention, the epoxide used or its open-chain precursor is preferably selected so that the desired bicalutamide is obtained directly when reacting with the p-fluorophenyl sulfinate. In this case, R in the general formulas (I) and (III) represents a radical of the formula (II)

However, the reaction according to the invention of the epoxide with the p-fluorophenyl sulfinate salt does not necessarily have to be at the end of the synthetic route for the production of bicalutamide. Therefore, R in general formulas (1) and (III) can also be chosen so that the product obtained in the reaction from the epoxy with the p-fluorophenyl sulfinate salt is suitable as a precursor for the further synthesis of bicalutamide. For this purpose, R is selected such that R is used as a precursor for a radical of the formula (II)

serves. A suitable precursor for a radical of the formula (II) is, for example, the radical -COY where Y is a group suitable for the subsequent amide formation. In this case, the intermediate product obtained in the reaction of the epoxide with the p-fluorophenyl sulfinate salt can easily be further reacted with 3-trifluoromethyl-4-cyanoaniline to give the desired bicalutamide. Particularly suitable precursors for a radical of the formula (II) are carboxyl, acid halides such as acid chloride, normal esters and activated esters. Suitable radicals are known to the person skilled in the art and can be selected in accordance with the reaction procedure. If in the process according to the invention not from an epoxide of the general formula (I) but from a precursor thereof, namely a compound of the general formula (III)

it is assumed that the leaving group X can be selected by the person skilled in the art in accordance with the chosen reaction conditions. Suitable leaving groups are known to those skilled in the art and include halogens such as e.g. Cl, Br and I, as well as reactive leaving groups such as Alkali and aryl sulfonates and especially mesylate, tosylate and brosylate.

Suitable starting materials in which X is a halogen are e.g. already known from WO 98/55153 or can be easily prepared from the epoxy precursor using conventional organic chemistry processes.

Suitable starting materials in which X is a common leaving group such as is a mesylate, brosylate or tosylate group, are known from WO 01/00608 and can be obtained from the corresponding alcohol precursor by means of conventional organic chemistry processes.

If, instead of the epoxy precursor, the epoxide is to be used directly in the process according to the invention, this can be obtained, for example, as described in EP 0 100 172. The p-fluorophenyl sulfinate salts used according to the invention are preferably ammonium p-fluorophenyl sulfinate, alkaline earth p-fluorophenyl sulfinates or alkali p-fluorophenyl sulfinates and particularly preferably sodium p-fluorophenyl sulfinate. This can be done in a known way, for example to Olah, Paviath, Acta Chim. Hung. 4 [1954] pp. 111-117, can be obtained in very good yield.

The method according to the invention also has the advantage that the opening of the epoxide does not influence the sterochemical center already present in the epoxy, so that the method according to the invention both for the preparation of the (+) - bicalutamide and for the preparation of the R - (-) - or the S - (+) - bicalutamide can be used. The only thing that matters here is whether the racemic epoxide or its halohydrin precursor or a corresponding optically active R or S epoxide or the corresponding optically active halohydrin precursor is used as a starting material. The inventive reaction of the epoxide with the p-fluorophenyl sulfinate salt is preferably carried out in a suitable solvent, such as e.g. Methanol or DMF, in the presence of an acid such as e.g. Glacial acetic acid, at room temperature or with heating.

In a preferred embodiment of the invention, the epoxide of the general formula (I) is reacted with sodium p-fluorophenyl sulfinate for about 5 hours in a suitable solvent such as methanol after the addition of glacial acetic acid with heating to about 50 ° C. After completion of the reaction, the reaction mixture is worked up by removing the volatile constituents by an aqueous-organic extraction process. The crude product obtained after stripping off the organic solvent is recrystallized from a suitable solvent, for example from diisopropyl ether, to give pure bicalutamide. This reaction is illustrated by the reaction scheme below:

In a further preferred embodiment of the process according to the invention, the corresponding oxirane is first generated in situ from an open-chain compound of the general formula (IN) (for example by heating the compound of the general formula (III) with potassium tert-butoxide in toluene). In a second step, without isolation of the oxirane formed, this is then treated with sodium p-fluorophenyl sulfinate in a suitable solvent, such as e.g. Dimethylformamide (DMF), after adding glacial acetic acid at room temperature or slightly elevated temperature for about 16 h to react. This reaction is illustrated by the reaction scheme below:

The yield of bicalutamide is naturally better than with an intermediate isolation of the oxirane due to the fact that it is conducted as a one-pot reaction, since, for example, a normal workup loss is avoided when isolating the oxirane. The reaction residue can be worked up for example, after removing volatile constituents in dimethylformamide and diluted with water, the product crystallizing out. If necessary, further purification by recrystallization from a suitable solvent, such as diisopropyl ether, can follow.

The process according to the invention is explained in more detail by the following examples:

example 1

Synthesis of bicalutamide from the epoxy precursor

In a four-necked flask, 7.0 g (25.9 mmol) of N- (4'-cyano-3'-trifluoromethylphenyl) -2-methyl-oxirane-2-carboxamide, 9.43 g (51.8 mmol) of sodium p-fluorophenyl sulfinate in 50 ml of methanol and 3 ml of glacial acetic acid and then heated under reflux for 5 hours.

After completion of the reaction, the reaction mixture is evaporated to dryness and the residue is taken up in 50 ml of CH ₂ Cl ₂ and 20 ml of water. The organic phase is washed several times with water and dried over MgS0. After the solvent has been stripped off, crude bicalutamide is obtained, which is recrystallized from diisopropyl ether for further purification.

Yield: 7.1 g

Melting point: 187 ° - 189 ° C

Purity: 96.6% (HPLC) Example 2

Synthesis of bicalutamide from the halohydrin precursor (one-pot variant)

3.07 g of 3-chloro-N- (4'-cyano-3-trifluoromethylphenyl) -2-hydroxypropionamide are suspended in 50 ml of toluene and heated to 80 ° C. 1, 12 g of potassium t-butoxide in 20 ml of toluene are then added with vigorous stirring over 30 min. Then the mixture is stirred for a further 30 min at the same temperature.

After cooling to room temperature, 3.64 g of sodium p-fluorophenyl sulfinate, 0.6 ml of glacial acetic acid and 50 ml of DMF are added; the suspension obtained is then stirred at 40 ° C. for 16 h. After the volatiles have been removed in vacuo, the residue is dissolved in a little DMF and then diluted with water. Bicalutamide precipitates out of the solution; the product is filtered off, washed with water and dried in vacuo.

Yield: 3.9 g

Melting point: 187 ° - 189 ° C

Purity: 95.8% (HPLC)

Claims

claims

1. A process for the preparation of N- (4'-cyano-3'-trifluoromethyl) -3- (4 "- fluorophenylsulfonyl) -2-hydroxy-2-methyl-propionamide (bicalutamide), characterized in that an epoxide of the general Formula (I)

wherein R is a radical of the formula (II)

2. Process for the preparation of N- (4'-cyano-3'-trifluoromethyl) -3- (4 "- fluorophenylsulfonyl) -2-hydroxy-2-methyl-propionamide (bicalutamide), characterized in that a compound of general Formula (III)

wherein R is a radical of the formula (II)

or is a precursor thereof and X is a leaving group, is reacted with a p-fluorophenyl sulfinate salt and, if R is a precursor of the radical of the formula (II), this is converted into a radical of the formula (II).

3. The method according to claim 1, characterized in that the epoxide of the general formula (I) from a compound of the general formula (III)

wherein R is as defined in claim 1 and X is a leaving group.

4. The method according to claim 3, characterized in that the reaction starting from the compound of general formula (III) to the reaction with the p-fluorophenyl sulfinate salt is carried out in a one-pot reaction.

5. The method according to any one of the preceding claims, characterized in that the precursor for the rest of the formula (II) is a radical -COY, wherein Y is a group suitable for amide formation.

6. The method according to claim 5, characterized in that the radical -COY is selected from the group consisting of carboxyl, acid halides, normal esters and activated esters.

7. The method according to any one of claims 2-6, characterized in that X is selected from the group consisting of halogens such as Cl, Br and I, and alkyl and aryl sulfonates such as mesylate, tosylate and brosylate.

8. The method according to any one of the preceding claims, characterized in that the epoxide of the general formula (I) or the compound of the general formula (III) in Form of their racemate or one of their optically active R or S enantiomers is used.

9. The method according to any one of the preceding claims, characterized in that the p-fluorophenyl sulfinate salt is used as alkali p-fluorophenyl sulfinate and in particular as sodium p-fluorophenyl sulfinate.

10. Use of p-fluorophenyl sulfinate salts for the preparation of bicalutamide.